Biomedical Engineering Reference
In-Depth Information
5.2.2
Dealing with Errors
New users of any MD program will likely encounter some errors in their first few
simulation runs. Although no solution can be given without knowing the specific
errors, it is possible to offer general guidance: one of the most error-prone steps in
an MD simulation is the system preparation. Any small mistake at this stage could
cause the simulation to crash within the first few picoseconds or render its result
invalid. For instance, a new residue or ligand may have been introduced without the
corresponding force field parameters. The transformation matrix used to generate
an oligomer of the protein may have been entered in the wrong order, and the
resulting protein monomers may be placed too close to each other. In such cases, one
must go back to the system preparation step and fix any problems with the starting
structure. Missing force field parameters may be obtained using tools provided by
the corresponding MD package or force field [
113
,
118
,
119
]; and the transformation
matrix can be checked against the initial pdb file.
The cause of some errors may be more difficult to decipher, an example of
which is the common error message “atom moving too fast,” given by the MD
program NAMD [
94
]. This error means that a certain atom, the index of which is
given along with the error message, has a velocity greater than the maximum value
defined by the program. Since the maximum value is set to be much higher than the
velocities from any realistic MD simulation, this error usually indicates structural
defects in the system. For instance, two atoms may be placed right on top of each
other and the resulting vdW force, which is repulsive at very short distance, will
cause the two atoms to “fly away” at a very high speed. Usually, the minimization
step described earlier can eliminate these close contacts effectively. However, some
structural defects may be too great to be completely removed by minimization, in
which case manual correction of the initial structure is required. It is also likely
that only a small part of the initial structure is incorrect, which tends to be the case
when new residues or ligands are involved. In these cases, the problematic region
in the structure can be difficult to spot, since the majority of the system will behave
normally. Often, when one couldn't locate the problematic structure, it is useful to
repeat the simulation with the trajectory written every step. Such a “slow motion”
picture of the system could help to pinpoint the exact cause of the problem.
6
Advanced Simulation Techniques
In this section, we will briefly introduce some advanced simulation techniques,
including enhanced sampling and free energy calculation methods. As the calcu-
lation of free energy often requires enhanced sampling to be performed along a
specific reaction coordinate, the distinction between these two types of methods is
not always clear. Therefore, in the following discussions, we will not attempt a strict
classification, but will focus on a few commonly used techniques and their specific
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